Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[OH:10].N1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>COCCOCCOC.[Cu].[Cu]I>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1ccc(Br)cc1
Agent: [Cu]
Agent: [Cu]I
Agent: [Na]
Solvent: COCCOCCOC
Solvent: c1ccncc1
Product: COc1ccc(Oc2ccc(F)cc2F)cc1

Procedure:
To a suspension of the anhydrous sodium salt of 206 g of 2,4-difluorophenol in 400 ml of diethylene glycol dimethyl ether are added 5 g of copper powder, 5 g of copper(I) iodide, 8 ml of pyridine and 393 g of 4-bromoanisole. With stirring, the reaction mixture is heated, under nitrogen, for 17 hours to 150°-155° C. After cooling, the reaction mixture is filtered over Hyflo and the bulk of the solvent is removed by vacuum distillation. The residue is dissolved in ether and the ethereal solution is washed repeatedly with 10% aqueous sodium hydroxide and then with water. The ethereal solution is dried over sodium sulfate and the solvent is removed by distillation. The residue is purified by chromatography over silica gel (eluant: 8:1 mixture of petroleum ether/diethyl ether). The solvent is removed by evaporation, to give the title compound in the form of a residual oil; nD22 =1.5466.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[O:10][N:9]=2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[CH:18][CH:17]=1.C=O.[C:35]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:15][C:11]1([CH3:14])[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:35])=[C:3]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])=[CH:20][CH:21]=3)[CH:4]=2)[C:12]1=[O:13]
Reactant: CC1(C)ON=C(c2ccc(N)c(-c3ccc(NC(=O)c4c(F)cccc4F)cc3)c2)C1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1ccc(C2=NOC(C)(C)C2=O)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
To a 0° C. solution of Example 134 (50 mg, 0.11 mmol, 1.0 eq) in methanol (5 mL) was added formaldehyde (37% aqueous solution) (10 μL, 0.12 mmol, 1.1 eq). After stirring for 30 min at room temperature, sodium cyanoborohydride (8 mg, 0.14 mmol, 1.2 eq) was added to the above reaction mixture followed by a catalytic amount of acetic acid. The resulting mixture was stirred at room temperature for 12 h. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate (10 mL) and washed with water (5 mL), brine (5 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum and the crude product was purified by column chromatography (silica gel, DCM:MeOH as eluent) to afford 8 mg of title compound 1HNMR (400 MHz, CDCl3) δ 8.07 (dd, J=8.5, 2.0 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.45-7.09 (m, 3H), 7.46-7.43 (m, 3H), 7.04 (t, J=8.0 Hz, 2H), 6.72 (d, J=8.5 Hz, 1H), 4.33 (s, 1H, D2O exchangeable), 2.86 (s, 3H), 1.45 (s, 6H); ESI-MS (m/z) 450 (MH)+.
Reaction SMILES: BrCC(=O)CC(NC1C(=O)[N:10]2C(C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=O)=C(/C=C/Cl)C[S:14][C@H:9]12)=O.[N:37]([O-])=O.[Na+].Br[CH2:42][C:43](=O)[C:44](=[N:76][OH:77])[C:45]([NH:47][CH:48]1[C:74](=[O:75])[N:50]2[C:51]([C:58]([O:60][CH:61]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[O:59])=[C:52](/[CH:55]=[CH:56]/[Cl:57])[CH2:53][S:54][C@H:49]12)=[O:46].C(OCC)(=O)C>C(Cl)Cl.C(O)(=O)C>[OH:77][N:76]=[C:44]([C:43]1[N:10]=[C:9]([NH2:37])[S:14][CH:42]=1)[C:45]([NH:47][CH:48]1[C:74](=[O:75])[N:50]2[C:51]([C:58]([O:60][CH:61]([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[O:59])=[C:52](/[CH:55]=[CH:56]/[Cl:57])[CH2:53][S:54][C@H:49]12)=[O:46]
Reactant: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Reactant: O=N[O-]
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(/C=C/Cl)CS[C@H]23)cs1
Reaction time: 0.1 h

Procedure:
To a solution of benzhydryl 7-(4-bromo-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (3.5 g) in a mixture of methylene chloride (32 ml) and acetic acid (12 ml) was dropwise added an aqueous solution (3 ml) of sodium nitrite (0.61 g) at -22° C. and the mixture was stirred for 6 minutes at the same temperature to give a reaction mixture containing benzhydryl 7-(4-bromo-2-hydroxyimino-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate. To the reaction mixture was added ethyl acetate (0.77 g). The mixture was stirred for 5 minutes at -20° C. and washed with water and 10% aqueous solution of sodium chloride successively, and a mixture of thiourea (0.54 g) and N,N-dimethylacetamide (7.0 ml) was added thereto at 36° C. The mixture was evaporated to remove methylene chloride. The residue was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-hydroxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (2.65 g).
Reaction SMILES: OCC(OC1C(C(C)C)CCC(C)C1)=O.C([Si](Cl)(C)C)(C)(C)C.[OH:24][CH2:25][C:26]([O:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:27].OCC(O[C@H]1CCCC[C@@H]1C1C=CC=CC=1)=O.[CH:58]([Si:61](Cl)([CH:65]([CH3:67])[CH3:66])[CH:62]([CH3:64])[CH3:63])([CH3:60])[CH3:59]>>[CH:58]([Si:61]([CH:65]([CH3:67])[CH3:66])([CH:62]([CH3:64])[CH3:63])[O:24][CH2:25][C:26]([O:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:27])([CH3:60])[CH3:59]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C(CO)O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CC1CCC(C(C)C)C(OC(=O)CO)C1
Agent: O=C(CO)O[C@H]1CCCC[C@@H]1c1ccccc1
Product: CC(C)[Si](OCC(=O)O[C@@H]1CCCC[C@H]1c1ccccc1)(C(C)C)C(C)C

Procedure:
In the same manner, 1a, 1b, and 1c(+) were prepared from the combinations of (-)-menthyl hydroxyacetate with tertbutyldimethylsilyl chloride, (-)-(1R,2S)-2-phenyl-1-cyclohexyl hydroxyacetate with tert-butyldimethylsilyl chloride, and (+)-(1S,2R)-2-phenyl-1-cyclohexyl hydroxyacetate with triisopropylsilyl chloride, respectively, in 90-95% yields.
Reaction SMILES: [BH4-].[Na+].[B].[N+:4]([C:7]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])([O-:6])=[O:5].C(OCC)(=O)C>O1CCCC1.O>[N+:4]([C:7]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:14][CH:13]=[CH:12][C:8]=1[CH2:9][OH:10])([O-:6])=[O:5]
Reactant: O=C(O)c1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [B]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CO)cccc1Oc1ccccc1Cl
Reaction time: 3 h
Yield: 97.6 %

Procedure:
Sodium borohydride (4.4 g) and boron trifluoridediethyl ether (23.7 ml) were added to a solution of 2-nitro-3-(2-chlorophenoxy)benzoic acid (11.3 g) in dried tetrahydrofuran (100 ml), and the mixture was stirred for 3 hrs. at room temperature. To the reaction mixture were added ethyl acetate (200 ml) and water (200 ml), and the mixture was filtered. The ethyl acetate layer was separated from the filtrate, washed with aqueous sodium bicarbonate and saline, dried and then evaporated in vacuo. The oily residue (15.1 g) was subjected to column chromatography on silica gel (150 g) and eluted with methylene chloride to give 2-nitro-3-(2-chlorophenoxy)benzyl alcohol (10.5 g).
Reaction SMILES: C1(S[C:8]2[CH:9]=[C:10]([CH:14]3[O:18][CH2:17][CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=2)C=CC=CC=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[C:22](C(OO)=O)[CH:21]=1.[S:30]([O-:34])([O-])(=[O:32])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:20]1([S:30]([C:12]2[CH:11]=[C:10]([CH:14]3[O:15][CH2:16][CH2:17][O:18]3)[CH:9]=[CH:8][CH:13]=2)(=[O:34])=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: c1ccc(Sc2cccc(C3OCCO3)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1cccc(C2OCCO2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 2-(3-phenylsulfanylphenyl)-[1,3]-dioxolane (1.0 g, 3.6 mmol) and dichloromethane (15 ml). Cool to about −78° C. Add a slurry of m-chloroperbenzoic acid (2.3 g, 7.2 mmol) in dichloromethane (10 ml). After 30 minutes, warm to room temperature then add a solution 1N of sodium thiosulfate (20 ml). After 15 minutes, add a solution of saturated sodium bicarbonate. Separate the organic layer and extract the aqueous layer with dichloromethane. combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with EtOAc to give the title compound.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][C:9]1[C:14]([N:15](C(OC(C)(C)C)=O)[NH:16]C(OC(C)(C)C)=O)=[CH:13][CH:12]=[CH:11][N:10]=1>CC(O)C.C(OCC)C>[ClH:1].[NH:15]([C:14]1[C:9]([CH3:8])=[N:10][CH:11]=[CH:12][CH:13]=1)[NH2:16]
Reactant: Cc1ncccc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1ncccc1NN
Yield: 100 %

Procedure:
is Hydrogen chloride in dioxane (5.67 mL, 22.67 mmol) was added to a solution of di-tert-butyl 1-(2-methylpyridin-3-yl)hydrazine-1,2-dicarboxylate (Intermediate V1) (733 mg, 2.27 mmol) in IPA (10 mL). The reaction mixture was heated at reflux for 20 mins. The reaction mixture was allowed to cool and then diluted with diethyl ether (30 mL). The resultant precipitate was collected by filtration and dried in vacuo to afford 3-hydrazinyl-2-methylpyridine hydrochloride (362 mg, 100%). 1H NMR (400 MHz, DMSO) δ 2.66 (3H, s), 7.80-7.83 (1H, m), 7.95-7.97 (1H, m), 8.23-8.25 (1H, m), 9.15 (1H, s), 11.30 (1H, s); no ion in LCMS (1NH missing).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccc(C2=NCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: BrCCCCCCOc1ccc(C2=NCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 114 %

Procedure:
A stirring suspension of 163 g (1.0 mole) of 4,5-dihydro-2-(4-hydroxyphenyl)oxazole and 276 g (2.0 mole) milled potassium carbonate in 750 ml acetonitrile was heated to reflux in a 5 liter round-bottomed flask. A total of 457.5 ml (3.0 mole) of 1,6-dibromohexane was added all at once and reflux continued for 1 hour. The reaction mixture was filtered and the cake of inorganic salts washed with 100 ml of acetonitrile. The filtrate was evaporated on a rotary evaporator (bath temperature <40° C.) and the resulting residue slurried in 1.6 liters of hexane and chilled to 0° C. The resulting white solid was filtered and washed with 500 ml cold hexane. The recovery was 263 g (80%) of white solid. A total of 535 g of crude product was slurried in 1.1 liter of refluxing tert-butyl methyl ether. The mixture was allowed to cool to 30° C. and filtered with suction. The filtrate was cooled to 0° C. and the product crystallized. The solid was filtered off and dried to yield 372 g (70% recovery) of 2-[4-(6-bromohexyloxy)phenyl]-4,5-dihydro-oxazole, m.p. 79°-81° C. The crude product can also be recrystallized from acetonitrile. This removes excess dibromohexane and most of an undesired byproduct formed by reaction of 1 mole of dibromohexane with 2 moles of 4,5-dihydro-2-(4-hydroxyphenyl)oxazole, namely 1,6-bis[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexane, m.p. 174°-175° C. when isolated and purified.
Reaction SMILES: [O:1]=[C:2]1[NH:5][C@@H:4]([CH2:6]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:3]1[NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N-:29]=[N+:30]=[N-:31].[Na+].CN(C)C=O.C(OCC)(=O)C>C(Cl)Cl>[N:29]([CH2:6][C@H:4]1[C@@H:3]([NH:18][C:19](=[O:28])[CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:2](=[O:1])[NH:5]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)COc2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Reaction time: 24 h

Procedure:
A mixture containing 1.131 g (2.8 mmole) of cis-4-oxo-3-phenoxyacetylamino-2-p-toluenesulfonyloxymethylazetidine, 0.961 g (14.8 mmole) of sodium azide and 25 ml of anhydrous N,N-dimethylformamide was heated under argon at 40° for 6 hours then at ambient temperature for 24 hours. The reaction mixture was poured into ethyl acetate and was washed with water. The combined aqueous washes were extracted once with ethyl acetate and the ethyl acetate fractions were combined and extracted with brine. After drying the ethyl acetate solution (MgSO4) and filtering, the solvent was removed in vacuo to afford a yellow semi-crystalline residue. This residue was slurried in methylene dichloride and chromatographed on 25 g of silica gel (70-230 mesh). The 1:1 ethyl acetate:methylene dichloride fractions afforded the title compound; tlc: ethyl acetate, silica gel GF, Rf=0.38; mp 142°-143° (dec) (ethyl acetate-hexane).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH:5]=[CH2:6].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[Si:20]([O:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH:5]=[CH2:6])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: C=CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of (S)-tert-butyl 1-hydroxypent-4-en-2-ylcarbamate (165 g, 0.82 mol) and imidazole (72.5 g, 1.07 mol) in DCM (3 L) was added TBS-Cl (135.4 g, 0.9 mol). The reaction was stirred at RT overnight and filtered. The filtrate was concentrates. The resulting residue was dissolved in EtOAc (L) and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-ylcarbamate (222.0 g), which was used in the next step without further purification. LRMS (M+H+) m/z 316.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:7]=1.[Br:14]Br.Cl>C(=O)([O-])[O-].[K+].[K+]>[F:13][C:2]([F:1])([F:12])[C:3]1[NH:4][C:5]([C:8]([F:9])([F:10])[F:11])=[C:6]([Br:14])[N:7]=1
Reactant: FC(F)(F)c1cnc(C(F)(F)F)[nH]1
Reactant: BrBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1nc(Br)c(C(F)(F)F)[nH]1
Yield: 64 %

Procedure:
2,5-bistrifluoromethylimidazole is dissolved in an aqueous solution of potassium carbonate. Bromine 1.1 equivalents is added and heated until color dissipates. Solution is acidified with dilute hydrochloric acid and extracted with ether. The ether layer is washed once with brine solution, dried over sodium sulfate and stripped to give product in 64% yield.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.C[SH+]C1C=CC(O[C:21](=[O:35])[C@H:22]([CH3:34])[NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=CC=1.[NH2:36][C@H:37]([C:41]([OH:43])=[O:42])[CH:38]([CH3:40])[CH3:39].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:36][C@H:37]([C:41]([OH:43])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[CH3:34])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[SH+]c1ccc(OC(=O)[C@H](C)NC(=O)OCc2ccccc2)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
In 50 ml of chloroform was dissolved 4.14 g of benzyloxycarbonylalanine p-methylsulfoniophenyl ester p-toluenesulfonate, and 20 ml of an aqueous solution of 0.91 g of valine and 1.1 ml of triethylamine was dropwise added thereto under stirring at room temperature. The reaction mixture was stirred for 8 hours at room temperature and then separated. The chloroform layer was washed with water, dried, and concentrated under reduced pressure, and ether was added to the residue to afford white crystals.
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[C:14]([Cl:22])[CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1.N.[NH2:24][C:25]([NH2:27])=[O:26]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N.ClCCl>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:20])[F:21])=[C:14]([Cl:22])[CH:13]=3)[CH2:11][O:26][C:25]([NH2:27])=[N:24]2)[CH:7]=[CH:8][CH:9]=1
Reactant: C=C(c1cccc(Br)c1)c1ccc(OC(F)F)c(Cl)c1
Reactant: NC(N)=O
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: NC1=NC(c2cccc(Br)c2)(c2ccc(OC(F)F)c(Cl)c2)CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of iodine (1.71 g, 6.74 mmol) in ethyl acetate (40 mL) was added dropwise over 25 min to a mixture of 4-[1-(3-bromo-phenyl)-vinyl]-2-chloro-1-difluoromethoxy-benzene (2.2 g, 6.13 mmol) and silver cyanate (1.10 g, 7.35 mmol) in acetonitrile (24 mL) and ethyl acetate (11 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 50 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 60° C. for 4 hours. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline. Dichloromethane (40 mL) was added to the crude and the two phases were separated; organic layer was collected, dried over magnesium sulfate anhydrous, filtered and evaporated under reduced pressure. The crude product was purified by silica gel chromatography eluting with dichloromethane/methanol (gradient: 0-6%) to give 1.02 g of desired product as a yellow oil (40%)
Reaction SMILES: [C-]#N.[Na+].[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[C:13](#[N:16])[CH:14]=[CH2:15].C(O)(=O)C>CN(C)C=O.O>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([C:9](=[O:10])[CH2:15][CH2:14][C:13]#[N:16])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C=CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N#CCCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of freshly ground sodium cyanide (0.75 g, 15.0 mmol) in dimethylformamide (DMF) is added, over 30 min., 4-chlorobenzaldehyde (21.0 g, 150.0 mmol) in DMF. 30 Minutes after the addition is completed, acrylonitrile (5.96 g, 7.4 ml, 112.5 mmol) is added over a period of 1 hour. The mixture is stirred at RT for 3 hours, after which acetic acid (0.99 g, 0.94 ml, 16.5 mmol) is added. After 5 min., the reaction mixture is poured into water and extracted with chloroform. The combined chloroform layers are washed with water and with brine, dried and stripped of solvent. The residue is recrystallized and filtered to give 4-(4-chlorophenyl)-4-oxobutyronitrile.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)#[N:2].[CH2:20]([OH:22])[CH3:21]>>[ClH:18].[ClH:18].[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:4]([OH:11])([CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH2:3][C:1](=[NH:2])[O:22][CH2:20][CH3:21]
Reactant: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CCO
Product: CCOC(=N)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1 g) was dissolved in dry ethyl alcohol (100 ml) and dry hydrogen chloride gas was bubbled in, at 0° C., for 10 minutes. The reaction mixture was then stirred at room temperature overnight, and then the solvent was decanted from the solid. The solid was then washed with dry ether and dried to yield the title compound, (1.15 g), m.p. 154°-156° C. Found: C,40.6; H,4.4; N,13.6. Calculated for C14H16Cl2N4O2.2HCl: C,40.4; H,4.4; N,13.5%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[N:12]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:21]([CH2:24][C:25](=[O:27])[CH3:26])(=[O:23])[CH3:22]>O.Cl.C(O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][N:12]=[C:24]([C:25](=[O:27])[CH3:26])[C:21](=[O:23])[CH3:22]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)C(=NNc1ccccc1C(F)(F)F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of 2-(trifluoromethyl)aniline (1.09 g, 6.80 mmol) in 5 mL of water and 5 mL of concentrated hydrochloride solution, sodium nitrite (563 mg, 8.16 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (1.67 g, 20.40 mmol) and acetylacetone (748 mg, 7.48 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-{[2-(trifluoromethyl)phenyl]hydrazono}pentane-2,4-dione (634 mg, 33%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11].C(C1C=CC=CN=1)(=O)C.[NH2:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31]#[N:32]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]2[CH:28]=[N:29][C:30]([C:31]#[N:32])=[C:26]2[N:25]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Reactant: N#Cc1[nH]cnc1N
Agent: CC(=O)c1ccccn1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccccn3)nc12
Yield: 46.7 %

Procedure:
Reaction of 1-pyridin-2-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 2-acetylpyridine according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (135 mg, 47%). MS (ISP) 289.9 [(M+H)+]; mp 205° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[N:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:21])=O.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][C:6]=2[Cl:21]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1cc[nH]c2cc(Br)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccnc2cc(Br)cnc12
Temperature: 95 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
7-bromo-1,5-naphthyridin-4(1H)-one (23.8 g, 105.8 mmol), acetonitriel (192 mL, 105.8 mmol), and DMF (2.05 mL, 26.5 mmol) were placed in a 3-necked round bottom flask set up with a reflux condenser. Argon bubbled through. Reaction mixture brought to reflux (˜95° C.). Oxalyl chloride (28.7 ml, 328.1 mmol) was added dropwise via addition funnel over 40 minutes and reaction allowed to stir at this temperature for 16 hrs. Reaction mixture cooled to 0° C. and basified to pH ˜8 with aqueous sodium bicarbonate solution. Product extracted with DCM (500 mL) three times. Organic layers combined, dried over sodium sulfate and concentrated to afford brown solid. This was purified by ISCO silica gel chromatography to afford 3-bromo-8-chloro-1,5-naphthyridine (3.6 g, 14% yield) as fluffy tan solid.